Restasis

Cyclosporine is a fine white powder. RESTASIS appears as a white opaque to slightly translucent homogeneous emulsion. It has an osmolality of 230-320 mOsmol/kg and a pH of 6.5-8.
Each mL of RESTASIS contains cyclosporine 0.05%.
RESTASIS (cyclosporine ophthalmic emulsion) 0.05% contains a topical immunomodulator with anti-inflammatory effects. Cyclosporine's chemical name is Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]. It has a molecular formula of C₆₂H₁₁₁N₁₁O₁₂ and molecular weight of 1202.6.
Excipients/Inactive Ingredients: Glycerin, castor oil, polysorbate 80, carbomer 1342, purified water and sodium hydroxide to adjust the pH.

Pharmacology: Pharmacodynamics: Mechanism of action: Cyclosporine is an immunosuppressive agent when administered systemically.
In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact mechanism of action is not known.
Pharmacokinetics: Blood cyclosporine A concentrations were measured using a specific high pressure liquid chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the samples collected, after topical administration of RESTASIS 0.05% BID, in humans for up to 12 months, were below the quantitation limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with RESTASIS.
Clinical Evaluations: Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 1200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS demonstrated statistically significant increases in Schirmer wetting of 10 mm versus vehicle at six months in patients whose tear production was presumed to be suppressed due to ocular inflammation. This effect was seen in approximately 15% of RESTASIS treated patients versus approximately 5% of vehicle-treated patients. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.
No increase in bacterial or fungal ocular infections was reported following administration of RESTASIS.
Toxicology: Preclinical Safety Data: Effects in non-clinical studies were observed following systemic administration only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Carcinogenesis and Mutagenesis studies: Systemic carcinogenicity studies were carried out in male and female mice and rats. In the 78-week oral (diet) mouse study, at doses of 1, 4 and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value.
In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. The low doses in mice and rats are approximately 300 and 80 times greater (normalized to body surface area), respectively, than the daily human dose, or alternatively, 1000 and 500 times greater, respectively, than the daily human dose of one drop of 0.05% RESTASIS BID into each eye.
Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e. induction of SCE), at high concentrations in this system.
Fertility Studies: No impairment in fertility was demonstrated in studies in male and female rats.

RESTASIS is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca (dry eye syndrome). Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.

Recommended Dose: The recommended dosage is 1 drop of RESTASIS twice a day in each eye approximately 12 hours apart.
Mode of Administration: The container should be inverted a few times before using to obtain a uniform, white, opaque emulsion.
Patients should be advised not to discontinue therapy prematurely.
If more than 1 topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Discard vial immediately after use.

Systemic overdose is unlikely to occur after ocular administration of RESTASIS. Due to low systemic concentrations of cyclosporine after topical treatment with RESTASIS, systemic intoxication from topical overdose in humans is not expected.

RESTASIS is contraindicated in patients with active ocular infections and in patients with known or suspected hypersensitivity to any of the ingredients in the formulation.

To avoid contamination or possible eye injury, do not touch tip of the vial to any surface and avoid contact with the eye.
RESTASIS has not been adequately studied in patients with a history of recurrent herpes keratitis.
RESTASIS should not be administered while the patient is wearing contact lenses. However, if contact lenses are worn, they should be removed prior to the administration of the emulsion. Lenses may be re-inserted at least 15 minutes after the administration of RESTASIS.
Effects on Ability to Drive and Use Machines: RESTASIS may cause transient blurring of vision which may impair the ability to drive or operate machines. The patient should wait until their vision has cleared before driving or using machinery.
Use in Children: The safety and efficacy of RESTASIS has only been studied in adults.
Use in the Elderly: No overall difference in safety or effectiveness has been observed between elderly and younger patients.

Pregnancy: There are no adequate data from the use of RESTASIS in pregnant women. Cyclosporine ophthalmic emulsion 0.05% is not absorbed systemically following topical ocular administration, and maternal use is not expected to result in fetal exposure to the drug. Studies in animals have shown reproductive toxicity at high maternotoxic dose.
Lactation: Cyclosporine is known to be excreted in human milk following systematic administration but excretion in milk after topical treatment has not been investigated. Although blood levels of cyclosporine are undetectable after topical administration of RESTASIS, caution should be exercised when RESTASIS is administered to a nursing mothers.

Clinical Studies: On combining the data from the pivotal phase III clinical studies, approximately 29% of treated patients experienced treatment related adverse events (adverse reactions) in the first year. The majority were ocular, mild or moderate in severity and none were serious. The most commonly reported adverse reaction was eye burning reported in approximately 17% of patients in the first year with the incidence of new reports decreasing to 5% at 2 years.
The frequency of adverse reactions observed during clinical trials involving 436 patients treated with RESTASIS is presented as follows.
The frequency is defined as follows: Very Common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very Rare (<1/10,000).
Nervous system disorders: Common: Headache.
Uncommon: Dizziness.
Eye disorders: Very common: Eye burning.
Common: Eye irritation, foreign body sensation in eye, ocular/conjunctival hyperaemia, eye pain, eye stinging, eye discharge, photophobia, eye pruritus, visual disturbance (blurred vision), dry eye.
Uncommon: Ulcerative keratitis, eyelid oedema, erythema of eyelid, lacrimation increased.
Gastrointestinal disorders: Uncommon: Nausea.
Skin and subcutaneous tissue disorders: Uncommon: Rash.
Postmarketing Experience: The following additional adverse reactions have been identified during postmarketing use of RESTASIS in clinical practice. Because postmarketing reporting of these reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions.
Eye Disorders: Eye swelling.
Immune System Disorders: Hypersensitivity.
Rare cases including severe angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea.
Injury, Poisoning and Procedural Complications: Superficial injury of the eye (from the vial tip touching the eye during administration).
Nervous System Disorders: Burning sensation.
Skin and Subcutaneous Tissue Disorders: Pruritus, urticaria.

No interaction studies have been performed.
Drugs that affect the cytochrome P-450 3A may alter cyclosporine metabolism. There is no detectable systemic absorption of RESTASIS following ocular administration. Therefore no interaction of topically applied RESTASIS with systemic drugs is expected to occur.

Store RESTASIS below 30°C.
Store unused vials in the original package (tray/carton).

Ophthalmic Decongestants, Anesthetics, Anti-Inflammatories

S01XA20 - artificial tears and other indifferent preparations ; Belongs to the class of other ophthalmologicals.

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